In this application, we hypothesize that two reciprocally regulated transcriptional factors, Sox4 and IRF4, play a central role in determining the quantity and quality of both murine and human cytotoxic T lymphocyte (CTL) responses. In addition, we will test the hypothesis that the dysregulated balance between IRF4 and Sox4 (i.e. diminished IRF4 and enhanced Sox4 expression) in CD4 and CD8 T cells impairs the development of Tfh and CTL responses in aged individuals, thereby leading to the age-associated defects in both humoral and cellular immunity following influenza vaccination. The goals of this application are to dissect the molecular mechanisms by which effective anti-viral CTL responses are induced during influenza infection, and to use immunological and pharmacological tools to simultaneously boost cellular and humoral immunity to increase influenza vaccine efficacy in aged individuals. Two specific Aims are proposed. Aim1: To elucidate the mechanisms by which the Sox4-IRF4 circuit controls the quantity and quality of anti-viral CTL responses during influenza infection. Aim 2: To define the T cell intrinsic role of PGE2/TGF-?ependent Sox4-IRF4 regulation in age-associated defects in humoral and cellular immunity following influenza vaccination. Relevance statement Seasonal influenza kills ~500,000 people globally and up to 50,000 people in the United States each year, most of deaths occur in the elderly. CD8 CTLs are required for efficient clearance of influenza virus infection and the levels of pre-existing CD8 CTLs in humans tightly correlate with the protection against symptomatic pandemic influenza. Thus, understanding the transcriptional programs regulating the efficient development of CTL responses during influenza infection and immunization has the potential for designing future influenza therapeutics and for improving influenza vaccine design. In addition, a major problem in influenza prevention is that elderly adults respond poorly to current influenza vaccines. As a result, even in a population with a high rate of influenza vaccination, influenza infection causes 10- to 30- times more hospitalizations in the elderly annually compared to younger individuals. Therefore, the successful completion of this application will shed light on the molecular basis underlying the age-associated defects in both humoral and cellular immunity following influenza vaccination. Furthermore, we expect that this application will establish principles that could be utilized in the future to improve the effiacy of influenza and other pathogen vaccines in aged individuals.